Project Summary/Abstract Forgetting is a dynamic and intrinsic cognitive process that allows humans and animals to make rapid and flexible behavioral choices. Imbalances in memory stability/retrieval vs forgetting may result in detrimental pathologies common in many neurological and psychiatric disorders. The neuroscience of active forgetting is underexplored; historically, experimental psychology studies have frequently posited forgetting as passive. Yet, recent findings in Drosophila challenge this notion and illustrate that forgetting is also active. One form of active forgetting, termed intrinsic forgetting, engages a small group of protocerebral posterior lateral 1 dopamine neurons (PPL1 DAn). The PPL1 DAn slowly and chronically erase labile olfactory memories after learning, but potently remove them when the neurons are stimulated. Two critical questions that remain unexplored is whether the forgetting signal from these DAns also impair the expression of consolidated protein-synthesis dependent long-term memories (PSD-LTM), and whether the impairment is due to memory erasure or a transient block in retrieval. My preliminary studies indicate that stimulating a single PPL1 DAn transiently inhibits the retrieval of PSD-LTM. Currently, knowledge about the neurobiological mechanisms that lead to transient forgetting does not exist. Thus, my initial observations offer the first entre, to our knowledge, of potential mechanisms that underly transient forgetting. This proposal is aimed to address these knowledge gaps. The overarching hypothesis is that transient forgetting is intrinsic to the fly?s memory management system and that factors extrinsic to the fly, such as interfering stimuli, can trigger the forgetting network to modulate the retrieval of PSD-LTM. To support my hypothesis, I will incorporate detailed behavioral and in vivo functional imaging assays, combined with multiple sophisticated genetic manipulations and novel paradigm designs. From Aim 1, I will confirm and extend my preliminary data indicating that only a single DAn in each brain hemisphere is responsible for transient forgetting. The data will reveal the minimal DAn components that are required for transient forgetting, which is essential for deeper experiments and to provide complete experimenter control over transient forgetting. From Aim 2, I will obtain data that will uncover the key DA receptor mediating the DAn-forgetting signal. Excitingly, I will identify the widely unchartered LTM cellular traces 3 days after spaced training and assay how these profiles change upon activating the DAn-forgetting pathway. These data may provide the molecular- and cellular-circuit based mechanisms that underscore transient forgetting. Lastly, from Aim 3, I will identify and characterize the extrinsic factors essential to induce top-down memory suppression to trigger transient memory loss. In sum, the outcomes of my proposed experiments will be the first to characterize the underlying extrinsic and intrinsic mechanisms that mobilize the DAn-forgetting pathway to cause transient memory loss.